The identity of so-called malignant stem cells in multiple myeloma has long been controversial. However, it is now appreciated that a small population of myeloma cells has a stem-like capacity for self-renewal and resides within the population of recognizable myeloma plasma cells, although whether these cells are quiescent or proliferative remains unresolved. It is also now accepted that subpopulations of myeloma plasma cells alternate bidirectionally and dynamically between immature and mature phenotypes, and both subpopulations are capable of clonogenicity in vitro and in animal models. Mounting evidence suggests that in multiple myeloma, small populations of quiescent myeloma stem cells behave as tumor-initiating cells as a result of their interaction with the endosteal bone marrow niche. However, a different, small population of proliferative myeloma stem cells produces the tumor bulk, and this population is likely responsible for the emergence of evolved subclones. A cellular-based plasticity model in which 2 states of stem-like cell compartments—quiescent and proliferative—exist simultaneously and are regulated dynamically by the microenvironment, epigenetics, and genetic aberrations may explain various clinical scenarios and the lack of consensus among some reported studies.